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1.
Proc Natl Acad Sci U S A ; 120(52): e2313514120, 2023 Dec 26.
Artículo en Inglés | MEDLINE | ID: mdl-38109538

RESUMEN

To cope with seasonal environmental changes, organisms have evolved approximately 1-y endogenous circannual clocks. These circannual clocks regulate various physiological properties and behaviors such as reproduction, hibernation, migration, and molting, thus providing organisms with adaptive advantages. Although several hypotheses have been proposed, the genes that regulate circannual rhythms and the underlying mechanisms controlling long-term circannual clocks remain unknown in any organism. Here, we show a transcriptional program underlying the circannual clock in medaka fish (Oryzias latipes). We monitored the seasonal reproductive rhythms of medaka kept under natural outdoor conditions for 2 y. Linear regression analysis suggested that seasonal changes in reproductive activity were predominantly determined by an endogenous program. Medaka hypothalamic and pituitary transcriptomes were obtained monthly over 2 y and daily on all equinoxes and solstices. Analysis identified 3,341 seasonally oscillating genes and 1,381 daily oscillating genes. We then examined the existence of circannual rhythms in medaka via maintaining them under constant photoperiodic conditions. Medaka exhibited approximately 6-mo free-running circannual rhythms under constant conditions, and monthly transcriptomes under constant conditions identified 518 circannual genes. Gene ontology analysis of circannual genes highlighted the enrichment of genes related to cell proliferation and differentiation. Altogether, our findings support the "histogenesis hypothesis" that postulates the involvement of tissue remodeling in circannual time-keeping.


Asunto(s)
Oryzias , Animales , Oryzias/genética , Estaciones del Año , Ritmo Circadiano/fisiología , Gónadas , Fotoperiodo
2.
NPJ Syst Biol Appl ; 9(1): 59, 2023 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-37993458

RESUMEN

The pair-wise observation of the input and target values obtained from the same sample is mandatory in any prediction problem. In the biomarker discovery of Alzheimer's disease (AD), however, obtaining such paired data is laborious and often avoided. Accumulation of amyloid-beta (Aß) in the brain precedes neurodegeneration in AD, and the quantitative accumulation level may reflect disease progression in the very early phase. Nevertheless, the direct observation of Aß is rarely paired with the observation of other biomarker candidates. To this end, we established a method that quantitatively predicts Aß accumulation from biomarker candidates by integrating the mostly unpaired observations via a few-shot learning approach. When applied to 5xFAD mouse behavioral data, the proposed method predicted the accumulation level that conformed to the observed amount of Aß in the samples with paired data. The results suggest that the proposed model can contribute to discovering Aß predictability-based biomarkers.


Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Ratones , Animales , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/genética , Encéfalo/metabolismo , Biomarcadores
3.
Cell Rep ; 42(7): 112707, 2023 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-37433294

RESUMEN

During development, positional information directs cells to specific fates, leading them to differentiate with their own transcriptomes and express specific behaviors and functions. However, the mechanisms underlying these processes in a genome-wide view remain ambiguous, partly because the single-cell transcriptomic data of early developing embryos containing accurate spatial and lineage information are still lacking. Here, we report a single-cell transcriptome atlas of Drosophila gastrulae, divided into 77 transcriptomically distinct clusters. We find that the expression profiles of plasma-membrane-related genes, but not those of transcription-factor genes, represent each germ layer, supporting the nonequivalent contribution of each transcription-factor mRNA level to effector gene expression profiles at the transcriptome level. We also reconstruct the spatial expression patterns of all genes at the single-cell stripe level as the smallest unit. This atlas is an important resource for the genome-wide understanding of the mechanisms by which genes cooperatively orchestrate Drosophila gastrulation.


Asunto(s)
Gástrula , Transcriptoma , Animales , Transcriptoma/genética , Drosophila/genética , Gastrulación/genética , Perfilación de la Expresión Génica , Regulación del Desarrollo de la Expresión Génica
4.
Nat Commun ; 14(1): 1924, 2023 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-37024462

RESUMEN

Wnt signaling is required to maintain bipotent progenitors for neural and paraxial mesoderm cells, the neuromesodermal progenitor (NMP) cells that reside in the epiblast and tailbud. Since epiblast/tailbud cells receive Wnt ligands produced by one another, this exchange may average out the heterogeneity of Wnt signaling levels among these cells. Here, we examined this possibility by replacing endogenous Wnt3a with a receptor-fused form that activates signaling in producing cells, but not in neighboring cells. Mutant mouse embryos show a unique phenotype in which maintenance of many NMP cells is impaired, although some cells persist for long periods. The epiblast cell population of these embryos increases heterogeneity in Wnt signaling levels as embryogenesis progresses and are sensitive to retinoic acid, an endogenous antagonist of NMP maintenance. Thus, mutual intercellular exchange of Wnt ligands in the epiblast cell population reduces heterogeneity and achieves robustness to environmental stress.


Asunto(s)
Estratos Germinativos , Mesodermo , Ratones , Animales , Diferenciación Celular/genética , Desarrollo Embrionario/genética , Vía de Señalización Wnt/fisiología , Regulación del Desarrollo de la Expresión Génica
5.
Sci Adv ; 9(10): eade5420, 2023 03 10.
Artículo en Inglés | MEDLINE | ID: mdl-36897945

RESUMEN

To obtain more of a particular uncertain reward, animals must learn to actively overcome the lack of reward and adjust behavior to obtain it again. The neural mechanisms underlying such coping with reward omission remain unclear. Here, we developed a task in rats to monitor active behavioral switch toward the next reward after no reward. We found that some dopamine neurons in the ventral tegmental area exhibited increased responses to unexpected reward omission and decreased responses to unexpected reward, following the opposite responses of the well-known dopamine neurons that signal reward prediction error (RPE). The dopamine increase reflected in the nucleus accumbens correlated with behavioral adjustment to actively overcome unexpected no reward. We propose that these responses signal error to actively cope with lack of expected reward. The dopamine error signal thus cooperates with the RPE signal, enabling adaptive and robust pursuit of uncertain reward to ultimately obtain more reward.


Asunto(s)
Dopamina , Recompensa , Ratas , Animales , Área Tegmental Ventral/fisiología , Núcleo Accumbens/fisiología , Aprendizaje/fisiología
6.
PLoS One ; 18(2): e0281319, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36827272

RESUMEN

The last three years have been spent combating COVID-19, and governments have been seeking optimal solutions to minimize the negative impacts on societies. Although two types of testing have been performed for this-follow-up testing for those who had close contact with infected individuals and mass-testing of those with symptoms-the allocation of resources has been controversial. Mathematical models such as the susceptible, infectious, exposed, recovered, and dead (SEIRD) model have been developed to predict the spread of infection. However, these models do not consider the effects of testing characteristics and resource limitations. To determine the optimal testing strategy, we developed a testing-SEIRD model that depends on testing characteristics and limited resources. In this model, people who test positive are admitted to the hospital based on capacity and medical resources. Using this model, we examined the infection spread depending on the ratio of follow-up and mass-testing. The simulations demonstrated that the infection dynamics exhibit an all-or-none response as infection expands or extinguishes. Optimal and worst follow-up and mass-testing combinations were determined depending on the total resources and cost ratio of the two types of testing. Furthermore, we demonstrated that the cumulative deaths varied significantly by hundreds to thousands of times depending on the testing strategy, which is encouraging for policymakers. Therefore, our model might provide guidelines for testing strategies in the cases of recently emerging infectious diseases.


Asunto(s)
COVID-19 , Humanos , Prueba de COVID-19 , SARS-CoV-2 , Modelos Teóricos , Hospitales
7.
iScience ; 26(1): 105754, 2023 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-36594030

RESUMEN

The immune system discriminates between harmful and harmless antigens based on past experiences; however, the underlying mechanism is largely unknown. From the viewpoint of machine learning, the learning system predicts the observation and updates the prediction based on prediction error, a process known as "predictive coding." Here, we modeled the population dynamics of T cells by adopting the concept of predictive coding; conventional and regulatory T cells predict the antigen concentration and excessive immune response, respectively. Their prediction error signals, possibly via cytokines, induce their differentiation to memory T cells. Through numerical simulations, we found that the immune system identifies antigen risks depending on the concentration and input rapidness of the antigen. Further, our model reproduced history-dependent discrimination, as in allergy onset and subsequent therapy. Taken together, this study provided a novel framework to improve our understanding of how the immune system adaptively learns the risks of diverse antigens.

8.
Nat Comput Sci ; 3(5): 418-432, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-38177842

RESUMEN

Humans and animals are not always rational. They not only rationally exploit rewards but also explore an environment owing to their curiosity. However, the mechanism of such curiosity-driven irrational behavior is largely unknown. Here, we developed a decision-making model for a two-choice task based on the free energy principle, which is a theory integrating recognition and action selection. The model describes irrational behaviors depending on the curiosity level. We also proposed a machine learning method to decode temporal curiosity from behavioral data. By applying it to rat behavioral data, we found that the rat had negative curiosity, reflecting conservative selection sticking to more certain options and that the level of curiosity was upregulated by the expected future information obtained from an uncertain environment. Our decoding approach can be a fundamental tool for identifying the neural basis for reward-curiosity conflicts. Furthermore, it could be effective in diagnosing mental disorders.


Asunto(s)
Conducta Exploratoria , Recompensa , Humanos , Animales , Ratas , Incertidumbre
9.
Commun Biol ; 5(1): 1268, 2022 11 18.
Artículo en Inglés | MEDLINE | ID: mdl-36400843

RESUMEN

Tissue stem cells maintain themselves through self-renewal while constantly supplying differentiating cells. Two distinct models have been proposed as mechanisms of stem cell homeostasis. According to the classical model, there is hierarchy among stem cells, and master stem cells produce stem cells by asymmetric division; whereas, according to the recent model, stem cells are equipotent and neutrally compete. However, the mechanism remains controversial in several tissues and species. Here, we developed a mathematical model linking the two models, named the hierarchical neutral competition (hNC) model. Our theoretical analysis showed that the combination of the hierarchy and neutral competition exhibited bursts in clonal expansion, which was consistent with experimental data of rhesus macaque hematopoiesis. Furthermore, the scaling law in clone size distribution, considered a unique characteristic of the recent model, was satisfied even in the hNC model. Based on the findings above, we proposed the criterion for distinguishing the three models based on experiments.


Asunto(s)
Hematopoyesis , Células Madre , Animales , Macaca mulatta , Homeostasis , Células Cultivadas
10.
Stem Cell Reports ; 17(9): 1924-1941, 2022 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-35931081

RESUMEN

A small number of offspring are born from the numerous sperm generated from spermatogonial stem cells (SSCs). However, little is known regarding the rules and molecular mechanisms that govern germline transmission patterns. Here we report that the Trp53 tumor suppressor gene limits germline genetic diversity via Cdkn1a. Trp53-deficient SSCs outcompeted wild-type (WT) SSCs and produced significantly more progeny after co-transplantation into infertile mice. Lentivirus-mediated transgenerational lineage analysis showed that offspring bearing the same virus integration were repeatedly born in a non-random pattern from WT SSCs. However, SSCs lacking Trp53 or Cdkn1a sired transgenic offspring in random patterns with increased genetic diversity. Apoptosis of KIT+ differentiating germ cells was reduced in Trp53- or Cdkn1a-deficient mice. Reduced CDKN1A expression in Trp53-deficient spermatogonia suggested that Cdkn1a limits genetic diversity by supporting apoptosis of syncytial spermatogonial clones. Therefore, the TRP53-CDKN1A pathway regulates tumorigenesis and the germline transmission pattern.


Asunto(s)
Células Madre Germinales Adultas , Semen , Animales , Apoptosis/genética , Masculino , Ratones , Espermatogénesis/genética , Espermatogonias/metabolismo , Espermatozoides
11.
Nat Commun ; 12(1): 3731, 2021 06 17.
Artículo en Inglés | MEDLINE | ID: mdl-34140477

RESUMEN

Decoding spatial transcriptomes from single-cell RNA sequencing (scRNA-seq) data has become a fundamental technique for understanding multicellular systems; however, existing computational methods lack both accuracy and biological interpretability due to their model-free frameworks. Here, we introduce Perler, a model-based method to integrate scRNA-seq data with reference in situ hybridization (ISH) data. To calibrate differences between these datasets, we develop a biologically interpretable model that uses generative linear mapping based on a Gaussian mixture model using the Expectation-Maximization algorithm. Perler accurately predicts the spatial gene expression of Drosophila embryos, zebrafish embryos, mammalian liver, and mouse visual cortex from scRNA-seq data. Furthermore, the reconstructed transcriptomes do not over-fit the ISH data and preserved the timing information of the scRNA-seq data. These results demonstrate the generalizability of Perler for dataset integration, thereby providing a biologically interpretable framework for accurate reconstruction of spatial transcriptomes in any multicellular system.


Asunto(s)
Biología Computacional/métodos , Perfilación de la Expresión Génica/métodos , Regulación del Desarrollo de la Expresión Génica/genética , Transcriptoma/genética , Algoritmos , Animales , Polaridad Celular/genética , Bases de Datos Genéticas , Drosophila melanogaster , Hibridación in Situ , Hígado/crecimiento & desarrollo , Hígado/metabolismo , Ratones , Modelos Teóricos , RNA-Seq , Análisis de la Célula Individual , Análisis Espacial , Corteza Visual/crecimiento & desarrollo , Corteza Visual/metabolismo , Pez Cebra/embriología , Pez Cebra/genética , Pez Cebra/metabolismo
12.
Sci Rep ; 11(1): 4069, 2021 02 18.
Artículo en Inglés | MEDLINE | ID: mdl-33603023

RESUMEN

Collective cell migration is a fundamental process in embryonic development and tissue homeostasis. This is a macroscopic population-level phenomenon that emerges across hierarchy from microscopic cell-cell interactions; however, the underlying mechanism remains unclear. Here, we addressed this issue by focusing on epithelial collective cell migration, driven by the mechanical force regulated by chemical signals of traveling ERK activation waves, observed in wound healing. We propose a hierarchical mathematical framework for understanding how cells are orchestrated through mechanochemical cell-cell interaction. In this framework, we mathematically transformed a particle-based model at the cellular level into a continuum model at the tissue level. The continuum model described relationships between cell migration and mechanochemical variables, namely, ERK activity gradients, cell density, and velocity field, which could be compared with live-cell imaging data. Through numerical simulations, the continuum model recapitulated the ERK wave-induced collective cell migration in wound healing. We also numerically confirmed a consistency between these two models. Thus, our hierarchical approach offers a new theoretical platform to reveal a causality between macroscopic tissue-level and microscopic cellular-level phenomena. Furthermore, our model is also capable of deriving a theoretical insight on both of mechanical and chemical signals, in the causality of tissue and cellular dynamics.


Asunto(s)
Movimiento Celular/fisiología , Células Epiteliales/fisiología , Animales , Comunicación Celular/fisiología , Células Epiteliales/metabolismo , Sistema de Señalización de MAP Quinasas , Modelos Biológicos , Cicatrización de Heridas/fisiología
13.
Dev Growth Differ ; 62(3): 177-187, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-32108939

RESUMEN

Vertebrate segments called somites are generated by periodic segmentation of the presomitic mesoderm (PSM). In the most accepted theoretical model for somite segmentation, the clock and wavefront (CW) model, a clock that ticks to determine particular timings and a wavefront that moves posteriorly are presented in the PSM, and somite positions are determined when the clock meets the posteriorly moving wavefront somewhere in the PSM. Over the last two decades, it has been revealed that the molecular mechanism of the clock and wavefront in vertebrates is based on clock genes including Hes family transcription factors and Notch effectors that oscillate within the PSM to determine particular timings and fibroblast growth factor (FGF) gradients, acting as the posteriorly moving wavefront to determine the position of somite segmentation. A clock-less condition in the CW model was predicted to form no somites; however, irregularly sized somites were still formed in mice and zebrafish, suggesting that this was one of the limitations of the CW model. Recently, we performed interdisciplinary research of experimental and theoretical biological studies and revealed the mechanisms of somite boundary determination in normal and clock-less conditions by characterization of the FGF/extracellular signal-regulated kinase (ERK) activity dynamics. Since features of the molecular clock have already been described in-depth in several reviews, we summarized recent findings regarding the role of FGF/ERK signaling in somite boundary formation and described our current understanding of how FGF/ERK signaling contributes to somitogenesis in normal and clock-less conditions in this review.


Asunto(s)
Tipificación del Cuerpo , Modelos Biológicos , Somitos/embriología , Somitos/metabolismo , Vertebrados/embriología , Animales , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Factores de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal , Vertebrados/metabolismo
14.
PLoS Comput Biol ; 15(2): e1006579, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30716091

RESUMEN

The reproducibility of embryonic development is remarkable, although molecular processes are intrinsically stochastic at the single-cell level. How the multicellular system resists the inevitable noise to acquire developmental reproducibility constitutes a fundamental question in developmental biology. Toward this end, we focused on vertebrate somitogenesis as a representative system, because somites are repeatedly reproduced within a single embryo whereas such reproducibility is lost in segmentation clock gene-deficient embryos. However, the effect of noise on developmental reproducibility has not been fully investigated, because of the technical difficulty in manipulating the noise intensity in experiments. In this study, we developed a computational model of ERK-mediated somitogenesis, in which bistable ERK activity is regulated by an FGF gradient, cell-cell communication, and the segmentation clock, subject to the intrinsic noise. The model simulation generated our previous in vivo observation that the ERK activity was distributed in a step-like gradient in the presomitic mesoderm, and its boundary was posteriorly shifted by the clock in a stepwise manner, leading to regular somite formation. Here, we showed that this somite regularity was robustly maintained against the noise. Removing the clock from the model predicted that the stepwise shift of the ERK activity occurs at irregular timing with irregular distance owing to the noise, resulting in somite size variation. This model prediction was recently confirmed by live imaging of ERK activity in zebrafish embryos. Through theoretical analysis, we presented a mechanism by which the clock reduces the inherent somite irregularity observed in clock-deficient embryos. Therefore, this study indicates a novel role of the segmentation clock in noise-resistant developmental reproducibility.


Asunto(s)
Tipificación del Cuerpo/fisiología , Desarrollo Embrionario/fisiología , Animales , Artefactos , Péptidos y Proteínas de Señalización del Ritmo Circadiano , Biología Evolutiva/métodos , Embrión de Mamíferos , Regulación del Desarrollo de la Expresión Génica/fisiología , Sistema de Señalización de MAP Quinasas , Mesodermo , Modelos Moleculares , Reproducibilidad de los Resultados , Somitos/fisiología , Pez Cebra/embriología
15.
PLoS Comput Biol ; 14(5): e1006122, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29718905

RESUMEN

Animals are able to reach a desired state in an environment by controlling various behavioral patterns. Identification of the behavioral strategy used for this control is important for understanding animals' decision-making and is fundamental to dissect information processing done by the nervous system. However, methods for quantifying such behavioral strategies have not been fully established. In this study, we developed an inverse reinforcement-learning (IRL) framework to identify an animal's behavioral strategy from behavioral time-series data. We applied this framework to C. elegans thermotactic behavior; after cultivation at a constant temperature with or without food, fed worms prefer, while starved worms avoid the cultivation temperature on a thermal gradient. Our IRL approach revealed that the fed worms used both the absolute temperature and its temporal derivative and that their behavior involved two strategies: directed migration (DM) and isothermal migration (IM). With DM, worms efficiently reached specific temperatures, which explains their thermotactic behavior when fed. With IM, worms moved along a constant temperature, which reflects isothermal tracking, well-observed in previous studies. In contrast to fed animals, starved worms escaped the cultivation temperature using only the absolute, but not the temporal derivative of temperature. We also investigated the neural basis underlying these strategies, by applying our method to thermosensory neuron-deficient worms. Thus, our IRL-based approach is useful in identifying animal strategies from behavioral time-series data and could be applied to a wide range of behavioral studies, including decision-making, in other organisms.


Asunto(s)
Conducta Animal/fisiología , Caenorhabditis elegans/fisiología , Toma de Decisiones/fisiología , Aprendizaje/fisiología , Refuerzo en Psicología , Taxia/fisiología , Animales , Biología Computacional
16.
Sci Rep ; 8(1): 4335, 2018 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-29531317

RESUMEN

During somite segmentation, clock genes oscillate within the posterior presomitic mesoderm (PSM). The temporal information ties up with the posteriorly moving FGF gradient, leading to the formation of a presumptive somite within the PSM. We previously investigated Erk activity downstream of FGF signaling by collecting stained zebrafish embryos, and discovered that the steep gradient of Erk activity was generated in the PSM, and the Erk activity border regularly shifted in a stepwise manner. However, since these interpretations come from static analyses, we needed to firmly confirm them by applying an analysis that has higher spatiotemporal resolutions. Here we developed a live imaging system for Erk activity in zebrafish embryos, using a Förster resonance energy transfer (FRET)-based Erk biosensor. With this system, we firmly showed that Erk activity exhibits stepwise regression within the PSM. Although our static analyses could not detect the stepwise pattern of Erk activity in clock-deficient embryos, our system revealed that, in clock-deficient embryos, the stepwise regression of Erk activity occurs at an irregular timing, eventually leading to formation of irregularly-sized somites. Therefore, our system overcame the limitation of static analyses and revealed that clock-dependent spatiotemporal regulation of Erk is required for proper somitogenesis in zebrafish.


Asunto(s)
Sistema de Señalización de MAP Quinasas , Somitos/enzimología , Proteínas de Pez Cebra/metabolismo , Pez Cebra/embriología , Pez Cebra/metabolismo , Animales , Técnicas Biosensibles/métodos , Tipificación del Cuerpo , Embrión no Mamífero/enzimología , Embrión no Mamífero/ultraestructura , Desarrollo Embrionario , Transferencia Resonante de Energía de Fluorescencia/métodos , Regulación del Desarrollo de la Expresión Génica , Proteínas de Pez Cebra/genética
17.
Biol Reprod ; 97(6): 902-910, 2017 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-29136097

RESUMEN

Vast amounts of sperm are produced from spermatogonial stem cells (SSCs), which continuously undergo self-renewal. We examined the possible effect of laterality in male germline transmission efficiency of SSCs using a spermatogonial transplantation technique. We transplanted the same number of wild-type and Egfp transgenic SSCs in the same or different testes of individual recipient mice and compared the fertility of each type of recipient by natural mating. Transgenic mice were born within 3 months after transplantation regardless of the transplantation pattern. However, transgenic offspring were born at a significantly increased frequency when wild-type and transgenic SSCs were transplanted separately. In addition, this type of recipient sired significantly more litters that consisted exclusively of transgenic mice, which suggested that left and right testes have different time windows for fertilization. Thus, laterality plays an important role in germline transmission patterns from SSCs.


Asunto(s)
Células Madre Germinales Adultas/trasplante , Espermatogonias/trasplante , Testículo/citología , Animales , Femenino , Fertilidad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos
18.
Dev Cell ; 43(3): 305-317.e5, 2017 11 06.
Artículo en Inglés | MEDLINE | ID: mdl-29112851

RESUMEN

The biophysical framework of collective cell migration has been extensively investigated in recent years; however, it remains elusive how chemical inputs from neighboring cells are integrated to coordinate the collective movement. Here, we provide evidence that propagation waves of extracellular signal-related kinase (ERK) mitogen-activated protein kinase activation determine the direction of the collective cell migration. A wound-healing assay of Mardin-Darby canine kidney (MDCK) epithelial cells revealed two distinct types of ERK activation wave, a "tidal wave" from the wound, and a self-organized "spontaneous wave" in regions distant from the wound. In both cases, MDCK cells collectively migrated against the direction of the ERK activation wave. The inhibition of ERK activation propagation suppressed collective cell migration. An ERK activation wave spatiotemporally controlled actomyosin contraction and cell density. Furthermore, an optogenetic ERK activation wave reproduced the collective cell migration. These data provide new mechanistic insight into how cells sense the direction of collective cell migration.


Asunto(s)
Movimiento Celular/fisiología , Células Epiteliales/citología , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Actomiosina/metabolismo , Animales , Perros , Activación Enzimática , Riñón/metabolismo , Fosforilación , Cicatrización de Heridas/fisiología
19.
PLoS Comput Biol ; 13(8): e1005702, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28792499

RESUMEN

Neural circuits are wired by chemotactic migration of growth cones guided by extracellular guidance cue gradients. How growth cone chemotaxis builds the macroscopic structure of the neural circuit is a fundamental question in neuroscience. I addressed this issue in the case of the ordered axonal projections called topographic maps in the retinotectal system. In the retina and tectum, the erythropoietin-producing hepatocellular (Eph) receptors and their ligands, the ephrins, are expressed in gradients. According to Sperry's chemoaffinity theory, gradients in both the source and target areas enable projecting axons to recognize their proper terminals, but how axons chemotactically decode their destinations is largely unknown. To identify the chemotactic mechanism of topographic mapping, I developed a mathematical model of intracellular signaling in the growth cone that focuses on the growth cone's unique chemotactic property of being attracted or repelled by the same guidance cues in different biological situations. The model presented mechanism by which the retinal growth cone reaches the correct terminal zone in the tectum through alternating chemotactic response between attraction and repulsion around a preferred concentration. The model also provided a unified understanding of the contrasting relationships between receptor expression levels and preferred ligand concentrations in EphA/ephrinA- and EphB/ephrinB-encoded topographic mappings. Thus, this study redefines the chemoaffinity theory in chemotactic terms.


Asunto(s)
Quimiotaxis/fisiología , Modelos Biológicos , Retina/fisiología , Transducción de Señal/fisiología , Colículos Superiores/fisiología , Animales , Axones/fisiología , Biología Computacional , Efrinas/metabolismo
20.
Nat Commun ; 8(1): 33, 2017 06 26.
Artículo en Inglés | MEDLINE | ID: mdl-28652571

RESUMEN

A long-standing question in neurodevelopment is how neurons develop a single axon and multiple dendrites from common immature neurites. Long-range inhibitory signaling from the growing axon is hypothesized to prevent outgrowth of other immature neurites and to differentiate them into dendrites, but the existence and nature of this inhibitory signaling remains unknown. Here, we demonstrate that axonal growth triggered by neurotrophin-3 remotely inhibits neurite outgrowth through long-range Ca2+ waves, which are delivered from the growing axon to the cell body. These Ca2+ waves increase RhoA activity in the cell body through calcium/calmodulin-dependent protein kinase I. Optogenetic control of Rho-kinase combined with computational modeling reveals that active Rho-kinase diffuses to growing other immature neurites and inhibits their outgrowth. Mechanistically, calmodulin-dependent protein kinase I phosphorylates a RhoA-specific GEF, GEF-H1, whose phosphorylation enhances its GEF activity. Thus, our results reveal that long-range inhibitory signaling mediated by Ca2+ wave is responsible for neuronal polarization.Emerging evidence suggests that gut microbiota influences immune function in the brain and may play a role in neurological diseases. Here, the authors offer in vivo evidence from a Drosophila model that supports a role for gut microbiota in modulating the progression of Alzheimer's disease.


Asunto(s)
Segmento Inicial del Axón/metabolismo , Señalización del Calcio , Calcio/metabolismo , Conos de Crecimiento/metabolismo , Neuritas/metabolismo , Proteínas de Unión al GTP rho/genética , Animales , Segmento Inicial del Axón/ultraestructura , Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina/genética , Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina/metabolismo , Comunicación Celular , Diferenciación Celular , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Embrión de Mamíferos , Regulación del Desarrollo de la Expresión Génica , Conos de Crecimiento/ultraestructura , Hipocampo/citología , Hipocampo/crecimiento & desarrollo , Hipocampo/metabolismo , Ratones , Ratones Endogámicos ICR , Factores de Crecimiento Nervioso/genética , Factores de Crecimiento Nervioso/metabolismo , Factores de Crecimiento Nervioso/farmacología , Neuritas/ultraestructura , Neurogénesis/genética , Imagen Óptica , Optogenética , Cultivo Primario de Células , Transporte de Proteínas , Factores de Intercambio de Guanina Nucleótido Rho/genética , Factores de Intercambio de Guanina Nucleótido Rho/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Unión al GTP rho/metabolismo , Proteína de Unión al GTP rhoA
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